Mutagen-Specific Mutation Signature Determines Global microRNA Binding

Micro-RNAs (miRNAs) are small non-coding RNAs that regulate gene products at the post-transcriptional level. It is thought that loss of cell regulation by miRNAs supports cancer development. Based on whole genome sequencing of a melanoma tumor, we predict, using three different computational algorithms, that the melanoma somatic mutations globally reduce binding of miRNAs to the mutated 3′UTRs. This phenomenon reflects the nature of the characteristic UV-induced mutation, C-to-T. Furthermore, we show that seed regions are enriched with Guanine, thus rendering miRNAs prone to reduced binding to UV-mutated 3′UTRs. Accordingly, mutation patterns in non UV-induced malignancies e.g. lung cancer and leukemia do not yield similar predictions. It is suggested that UV-induced disruption of miRNA-mediated gene regulation plays a carcinogenic role. Remarkably, dark-skinned populations have significantly higher GC content in 3′UTR SNPs than light-skinned populations, which implies on evolutionary pressure to preserve regulation by trans-acting oligonucleotides under conditions with excess UV radiation

NSCLC molecular testing in Central and Eastern European countries

Background: The introduction of targeted treatments for subsets of non-small cell lung cancer (NSCLC) has highlighted the importance of accurate molecular diagnosis to determine if an actionable genetic alteration is present. Few data are available for Central and Eastern Europe (CEE) on mutation rates, testing rates, and compliance with testing guidelines. Methods: A questionnaire about molecular testing and NSCLC management was distributed to relevant specialists in nine CEE countries, and pathologists were asked to provide the results of EGFR and ALK testing over a 1-year period. Results: A very high proportion of lung cancer cases are confirmed histologically/cytologically (75-100%), and molecular testing of NSCLC samples has been established in all evaluated CEE countries in 2014. Most countries follow national or international guidelines on which patients to test for EGFR mutations and ALK rearrangements. In most centers at that time, testing was undertaken on request of the clinician rather than on the preferred reflex basis. Immunohistochemistry, followed by fluorescent in situ hybridization confirmation of positive cases, has been widely adopted for ALK testing in the region. Limited reimbursement is a significant barrier to molecular testing in the region and a disincentive to reflex testing. Multidisciplinary tumor boards are established in most of the countries and centers, with 75-100% of cases being discussed at a multidisciplinary tumor board at specialized centers. Conclusions: Molecular testing is established throughout the CEE region, but improved and unbiased reimbursement remains a major challenge for the future. Increasing the number of patients reviewed by multidisciplinary boards outside of major centers and access to targeted therapy based on the result of molecular testing are other major challenges

Advances in the therapy of Alzheimer's disease: Targeting amyloid beta and tau and perspectives for the future

Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD

Vampires in the village Žrnovo on the island of Korčula: following an archival document from the 18th century

Središnja tema rada usmjerena je na raščlambu spisa pohranjenog u Državnom arhivu u Mlecima (fond: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) koji se odnosi na događaj iz 1748. godine u korčulanskom selu Žrnovo, kada su mještani – vjerujući da su se pojavili vampiri – oskvrnuli nekoliko mjesnih grobova. U radu se podrobno iznose osnovni podaci iz spisa te rečeni događaj analizira u širem društvenom kontekstu i prate se lokalna vjerovanja.The main interest of this essay is the analysis of the document from the State Archive in Venice (file: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) which is connected with the episode from 1748 when the inhabitants of the village Žrnove on the island of Korčula in Croatia opened tombs on the local cemetery in the fear of the vampires treating. This essay try to show some social circumstances connected with this event as well as a local vernacular tradition concerning superstitions

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3�6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55 of the global rise in mean BMI from 1985 to 2017�and more than 80 in some low- and middle-income regions�was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing�and in some countries reversal�of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories. © 2019, The Author(s)

Genome-wide analysis of fitness data and its application to improve metabolic models

Abstract Background Synthetic biology and related techniques enable genome scale high-throughput investigation of the effect on organism fitness of different gene knock-downs/outs and of other modifications of genomic sequence. Results We develop statistical and computational pipelines and frameworks for analyzing high throughput fitness data over a genome scale set of sequence variants. Analyzing data from a high-throughput knock-down/knock-out bacterial study, we investigate differences and determinants of the effect on fitness in different conditions. Comparing fitness vectors of genes, across tens of conditions, we observe that fitness consequences strongly depend on genomic location and more weakly depend on gene sequence similarity and on functional relationships. In analyzing promoter sequences, we identified motifs associated with conditions studied in bacterial media such as Casaminos, D-glucose, Sucrose, and other sugars and amino-acid sources. We also use fitness data to infer genes associated with orphan metabolic reactions in the iJO1366 E. coli metabolic model. To do this, we developed a new computational method that integrates gene fitness and gene expression profiles within a given reaction network neighborhood to associate this reaction with a set of genes that potentially encode the catalyzing proteins. We then apply this approach to predict candidate genes for 107 orphan reactions in iJO1366. Furthermore - we validate our methodology with known reactions using a leave-one-out approach. Specifically, using top-20 candidates selected based on combined fitness and expression datasets, we correctly reconstruct 39.7% of the reactions, as compared to 33% based on fitness and to 26% based on expression separately, and to 4.02% as a random baseline. Our model improvement results include a novel association of a gene to an orphan cytosine nucleosidation reaction. Conclusion Our pipeline for metabolic modeling shows a clear benefit of using fitness data for predicting genes of orphan reactions. Along with the analysis pipelines we developed, it can be used to analyze similar high-throughput data

A Synthetic Oligo Library and Sequencing Approach Reveals an Insulation Mechanism Encoded within Bacterial σ54 Promoters

We use an oligonucleotide library of >10,000 variants to identify an insulation mechanism encoded within a subset of σ54 promoters. Insulation manifests itself as reduced protein expression for a downstream gene that is expressed by transcriptional readthrough. It is strongly associated with the presence of short CT-rich motifs (3–5 bp), positioned within 25 bp upstream of the Shine-Dalgarno (SD) motif of the silenced gene. We provide evidence that insulation is triggered by binding of the ribosome binding site (RBS) to the upstream CT-rich motif. We also show that, in E. coli, insulator sequences are preferentially encoded within σ54 promoters, suggesting an important regulatory role for these sequences in natural contexts. Our findings imply that sequence-specific regulatory effects that are sparsely encoded by short motifs may not be easily detected by lower throughput studies. Such sequence-specific phenomena can be uncovered with a focused oligo library (OL) design that mitigates sequence-related variance, as exemplified herein

Invited Commentary: Human Papillomavirus Infection and Risk of Cervical Precancer—Using the Right Methods to Answer the Right Questions

Epidemiologists are well aware of the negative consequences of measurement error in exposure and outcome variables to their ability to detect putative causal associations. However, empirical proof that remedying the misclassification problem improves estimates of epidemiologic effect is seldom examined in detail. Of all areas in cancer epidemiology, perhaps the best example of the consequences of misclassification and of the steps taken to circumvent them was the pursuit, beginning in the mid-1980s, of the human papillomavirus (HPV) infection–cervical cancer association. The stakes were high: Had the wrong conclusions been reached epidemiologists would have been led astray in the search for competing hypotheses for the sexually transmissible agent causing cervical cancer or in ascribing to HPV infection a mere ancillary role among many lifestyle, hormonal, and environmental factors. The article by Castle et al. in this issue of the Journal (Am J Epidemiol. 2010;171(2):155–163) provides a detailed account of the joint influences of improved HPV and cervical precancer measurements in gradually unveiling the strong magnitude of the underlying association between viral exposure and cervical lesion risk. In this commentary, the authors extend the findings of Castle et al. by providing additional empirical evidence in support of their arguments